ArticleFrontiers in endocrinology2021
Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol.
Article in Frontiers in endocrinology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 8 citations in OpenAlex.
- Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects.Pharmacology research & perspectives · 2024Review
- Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.PLoS biology · 2024Article
- Impact of secretin receptor homo-dimerization on natural ligand binding.Nature communications · 2024Article
- Article
- Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.SLAS discovery : advancing life sciences R & D · 2022Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Drugs useful in prevention/treatment of obesity could improve health. Cholecystokinin (CCK) is a key regulator of appetite, working through the type 1 CCK receptor (CCK1R); however, full agonists have not stimulated more weight loss than dieting. We proposed an alternate strategy to target this receptor, while reducing likelihood of side effects and/or toxicity. Positive allosteric modulators (PAMs) with minimal intrinsic agonist activity would enhance CCK action, while maintaining spatial and temporal characteristics of physiologic signaling. This could correct abnormal stimulus-activity coupling observed in a high-cholesterol environment observed in obesity. We utilized high-throughput screening to identify a molecule with this pharmacological profile and studied its basis of action. Compound 1 was a weak partial agonist, with PAM activity to enhance CCK action at CCK1R, but not CCK2R, maintained in both normal and high cholesterol. Compound 1 (10 µM) did not exhibit agonist activity or stimulate internalization of CCK1R. It enhanced CCK activity by slowing the off-rate of bound hormone, increasing its binding affinity. Computational docking of Compound 1 to CCK1R yielded plausible poses. A radioiodinatable photolabile analogue retained Compound 1 pharmacology and covalently labeled CCK1R Thr
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Registered trials
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